Breast cancer cells metastasize to the bone marrow early in the course of the disease (Braun, S., et al. (2000) The New England J. Med. 342, 525-533). Most metastatic cells die upon reaching the marrow microenvironment, but some well-differentiated cells that survive can remain dormant, or growth arrested without loss of viability, for years (Boyce, B. F., et al. (1999) Endocrine-Related Cancer 6, 333-347; Chang, J., et al. (1999) J. Clinical Oncology 17, 3058-3063). They remain protected from death and, in fact, survive multiple rounds of adjuvant chemotherapy administered specifically to eradicate them (Braun, S., et al. (2000) J. Clin. Onc. 18, 80-86). The factors and the mechanisms that induce dormancy, that is, growth arrest coupled with long-term survival, of occult breast cancer cells in bone marrow microenvironment and which protect the cells from chemotherapy remain largely unknown. However, a variety of growth factors and ligands of cellular integrins in the marrow microenvironment may influence the fate of the metastatic cell. These factors have well-established effects on cell behavior, including protection of hematopoietic stem cells (Ploemacher, R. E. (1997) Baillieres Clinical Haematology 10, 429-444; Knaan-Shanzer, S., et al., (1999) Experimental Hematology 27, 1440-1450).
Bone marrow stroma is a rich source of growth factors such as epidermal growth factor (EGF), insulin-like growth factor (IGF-1) and basic fibroblast growth factor (FGF-2). FGF-2, a factor implicated in mammary ductal differentiation, induces growth arrest in a variety of relatively differentiated breast cancer cells.
However, there is a further need for identification of the factors responsible for growth arrest and long-term survival of occult cancer cells, as well as a better understanding of the mechanisms involved. Upon identification of the factors involved, novel therapeutics may be developed which could be used as stand-alone therapies or may be used as adjunct therapy with other standard forms of therapy to treat cancer or hyperproliferative disorders, such as chemotherapy or radiation therapy. It is with respect to this unmet need that the current invention is directed.
Other advantages of the present invention will become apparent from the ensuing detailed description taken in conjunction with the following illustrative drawings.